PROJECT SUMMARY Alzheimer's Disease is a neurodegenerative disease characterized by a progressive decline in cognitive function and a corresponding accumulation of ?-amyloid plaques and neurofibrillary tangles, the two hallmark pathologies. Drugs currently available to AD patients manage the disease symptoms by improving neuronal activity, but efficacy diminishes as the disease advances. In tauopathies such as AD, the accumulation of tau correlates closely with neuronal loss and decline of cognitive function. The novel targeted approach to AD drug development proposed by Aquinnah Pharmaceuticals stems from discoveries made by Dr. Ben Wolozin (Boston University and co-founder of Aquinnah) and his lab, in which tau pathology (in both AD brain samples and animal models) was observed to be present in stress granules (SG). Aquinnah is advancing these compelling findings to identify molecules that inhibit the formation of tau-SGs as a novel treatment for AD.!The overall objective of this SBIR Phase 1 application is to develop several different biologically-relevant tau-SG assays to select the most promising and biologically relevant hits from our currently ongoing HTS, which will then be evaluated further for exploratory ADME and brain penetration analysis. The successful completion of this Phase 1 SBIR will result in the identification of compounds that modulate tau-SGs and are candidates for a Phase 2 medicinal chemistry hit-to-lead and lead optimization program to further develop as novel drugs for the treatment of AD.